The specific aim of the present application is to validate plasma insulin-like growth factor-I (IGF-1) as a surrogate endpoint of contralateral breast cancer in women, aged less that 50 years, on intervention with the synthetic retinoid 4-(hydroxyphenyl) retinamide (fenretinide or 4-HPR). This will be accomplished by assessing the relationship between the incidence of contralateral breast cancer and the change in plasma concentrations of total or unbound IGF-I (the latter expressed as IGF-I/IGF binding protein-3 ratio). The analysis will be integrated into the ongoing phase III trial of a five-year intervention with 4-HPR at the daily dose of 200 mg. Previous pilot studies of 4-HPR have demonstrated a significant reduction of total and unbound IGF-I in women aged less than 50 years. In addition, an interim analysis of the ongoing, phase III trial involving 2,972 stage I breast cancer women aged 30-70 years indicates that 4-HPR reduces ovarian and contralateral breast cancers in young or premenopausal women. The sample on study will include a subgroup of 641 women aged less than 50 years (377 on 4-HPR intervention and 264 untreated controls) in whom plasma aliquot are available both at baseline and during the intervention period. The analysis will be performed after three years when the highest number of contralateral tumors will be available. Although contralateral breast cancer involves a selected target population, validation of the biomarker as an intermediate endpoint in this setting may provide insight into breast carcinogenesis. This may help to select more specific agents and to implement more efficient intervention trials with 4-HPR in the future, particularly a wider group of high risk subjects, including young women with genetic susceptibility to breast and ovarian cancers.